Importance: Flotation restricted environmental stimulation therapy (REST) is an emerging therapeutic intervention that, to our knowledge, has never been directly compared with an indistinguishable placebo in patients with chronic pain. Objective: To determine whether 5 flotation-REST sessions alleviate chronic pain. Design, Setting, and Participants: This single-blind, randomized clinical trial compared flotation-REST as an intervention for the treatment of chronic pain with indistinguishable placebo and wait-list control conditions at Hannover Medical School, Hannover, Germany. Men and women aged 18 to 75 years who had been diagnosed with chronic pain disorder with psychological and somatic factors (International Statistical Classification of Diseases and Related Health Problems, 10th Revision, German Modification, code F45.41) by physicians at the study center were randomly assigned to 1 of the 3 groups. Data were collected from June 26, 2018, to June 18, 2020. Interventions: Patients in the intervention and placebo groups underwent 5 treatment sessions lasting 60 to 90 minutes, each session separated by 4 days. The placebo treatment was delivered in the same floating tank but controlled for effortless floating and environmental stimulus restriction. Patients in the wait-list control group did not receive any additional treatment but were asked to continue any ongoing treatments at the time of enrollment. Main Outcomes and Measures: The primary outcome was a change in pain intensity 1 week after the last treatment session. The assessment was repeated at 12 and 24 weeks. Secondary outcomes included pain-related disability, pain area, pain widespreadness (number of body regions affected by pain), anxiety, depression, and quality of life, as well as several other short-term outcomes. Results: A total of 99 patients (mean [SD] age, 51.7 [12.3] years; 80 women [81%]) were included in the study. No differences were found among the groups in the primary outcomes (mean [SD] change in maximum pain: -7.6 [19.7] for the intervention group, -5.8 [12.7] for the placebo group, and 0.4 [14.0] for the wait-list control group; mean [SD] change in mean pain: -2.1 [19.4] for the intervention group,-4.2 [16.2] for the placebo group, and 2.0 [12.6] for the wait-list control group). Long-term secondary outcomes did not show significant differences. In the short term, patients in the intervention group showed significant improvements in pain intensity (-17.0 [17.1]; P < .001), relaxation (23.9 [22.6]; P < .001), anxiety (-10.1 [8.4]; P < .001), pain area (-3.6% [7.4%]; P < .001), and widespreadness (-2.0 [3.0]; P < .001), and similar changes where observed in the placebo group. Conclusions and Relevance: Patients with chronic pain experienced no long-term benefits from the 5 flotation-REST interventions. Clinically relevant short-term changes in pain in the placebo group suggest that improvements may not be caused by environmental stimulus restriction or effortless floating as previously thought. Trial Registration: ClinicalTrials.gov Identifier: NCT03584750.